Tumor growth, angiogenesis, and invasion depends on the recruitment and coordinated activity of different cell types populating the tumor stroma, such as endothelial cells, fibroblasts, pericytes, and infiltrating inflammatory cells. Although tumor associated vessels share similar components to normal vessels, including endothelial cells, basement membranes and pericytes, these vessels are abnormal, tortuous and leaky. While the functional role of endothelial cells in the context of tumor angiogenesis and vasculogenesis is extensively studied, the contribution of pericytes/perivascular cells in cancer progression and metastasis is poorly understood. Several studies suggest that targeting pericytes can control the rate of angiogenesis and growth of late stage tumors; however it is imperative to perform functional studies to evaluate the consequence of anti-pericyte therapy before moving these agents into clinical testing phase. In this regard, NG2, a novel cell surface chondroitin sulfate proteoglycan, is shown to be a reliable marker of pericytes/perivascular cells, along with the PDGF receptor 2 (PDGFR2). This grant proposes to perform functional studies utilizing these markers in transgenic mice setting to elucidate the role of pericytes in breast cancer progression and lung metastasis. This application will test the central hypothesis that pericytes associated with primary breast tumors determine the rate of cancer progression and emergence lung metastasis. The proposal will functionally explore therapeutic targeting of pericytes using novel genetic mouse models in combination with novel pharmacological interventions using targeted therapy. The specific aims in this proposal are: 1) To determine the functional contribution of pericytes in primary breast cancer progression and lung metastasis, 2) To investigate the contribution of epithelial to mesenchymal transition in hypoxia induced lung metastasis, and 3) To determine the role of PDGFR2 in lung metastasis. PUBLIC HEALTH RELEVANCE: About 80% of cancer deaths are associated with systemic disease, also known as 'metastasis'. Many studies suggest that the genetic alterations that accumulate in the cancer cells define, in part, the metastatic potential. Nevertheless, components of the tumor stroma, such as fibroblasts, endothelial cells, and pericytes, may play a role in metastasis. Several studies suggest pericytes as new potential therapeutic targets to inhibit tumor angiogenesis and subsequently tumor growth. Our proposal is designed to functionally determine the contribution of pericytes in primary tumor growth and metastasis, and identify new therapies to inhibit metastasis.